Topoisomerase I Inhibitors Show Promise Against Difficult-to-Treat CNS Tumors

Tuesday, May 1, 2001

Volume:

10

Issue:

5

DURHAM, North Carolina Topoisomerase I inhibitors have
shown promising activity in difficult-to-treat tumors of the central nervous
system (CNS), according to Henry
S. Friedman, MD. In studies
of camptothecins, both irinotecan (Camptosar) and topotecan (Hycamtin) showed "prodigious
activity" in slowing tumor growth and causing tumor regression in
subcutaneous xenografts of human gliomas, Dr. Friedman told those attending the
Vanderbilt University Symposium. Dr. Friedman is Jones B. Powell, Jr.,
Professor of Neuro-Oncology at Duke University Medical Center in Durham, North
Carolina.

"In studies of intracranial glioma xenografts, median
survival increased by 29% to 39% with topotecan, 114% with irinotecan, and by
48% with 9-aminocamptothecin (9-AC)," Dr. Friedman reported. "In
intracranial medulloblastoma xenografts, median survival increased by 25% with
9-AC and by 73% with irinotecan."

These preclinical studies led in 1998 to a phase II trial of
irinotecan in 60 patients with recurrent malignant glioma. Patients were
treated with irinotecan 125 mg/m2 weekly x 4, with 2 weeks’ rest between
cycles. Physical examinations and magnetic resonance imaging (MRI) studies were
performed every cycle.

"In these 60 patients there were 9 partial responses, 4
minimal responses, and 13 patients with stable disease," Dr. Friedman
said. "We thought there should have been a higher response rate. When we
examined the data more closely, we found that patients on the anticonvulsants
carbamazepine (Tegretol), phenobarbital, or gabapentin (Neurontin) actually had
irinotecan (SN-38) plasma levels about 25% of expected, so most of these
patients were being underdosed. An estimated irinotecan dose of 410 mg/m2/week
x 4 with a 2-week break would be needed for most patients on these
anticonvulsants, although there is considerable interpatient variability."

Combined with Carmustine

Irinotecan has also been combined with chloroethylating agents
such as carmustine in malignant glioma. Dr. Friedman said that a phase II trial
of irinotecan plus carmustine in patients with recurrent malignant glioma
showed that carmustine should be given first to achieve optimal effect from the
regimen.

In this trial, the carmustine dose was 100 mg/m2 on day 1.
Irinotecan was administered at 125 mg/m2 in patients not on anticonvulsants and
225 mg/m2 in patients on anticonvulsants, given on days 1, 8, 15, 22 and
skipping days 29 and 36. The combination significantly increased activity over
that seen with irinotecan alone.

Temozolomide (Temodar) has also been tested in combination with
irinotecan for treating malignant glioma. Dr. Friedman said that a phase I
trial will accrue patients into two strata, depending on whether the patient
uses carbamazepine, hydantoin (Dilantin), or phenobarbital, or not.

Irinotecan will be given prior
to temozolomide on day 1 of each cycle at 200 mg/m2/d x 5 days, every 6 weeks.
Irinotecan will be given in
4 weekly administrations followed
by a 2-week rest. Irinotecan doses
will escalate from 40 to 125 mg/m2/wk.